Melatonin (N-acetyl-5-methoxytryptamine) was discovered in plants in 1995; since then numerous functions have been attributed to this molecule in vascular plants. In addition to its recognized role as a universal antioxidant, other relevant functions have been studied in plants such as its rhizogenic- and vegetative-growth effects, protection against leaf senescence and influences on photosynthesis and on the stomatal apparatus. Also, melatonin has a protective role in stress situations (biotic and abiotic), acting as an osmoregulation and a metabolic corrector when confronted with different stresses. One of the most outstanding aspects is the involvement of melatonin as a multi-signaling molecule in plants. The dual roles of melatonin in physiological stress situations involve both its direct action (free of receptor action) as an antioxidant and its role as a regulator of gene expression. Its relationship with central elements of the plant redox network such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the regulation of relevant elements is discussed. All recent data on melatonin are incorporated to present an updated model, where the balance between ROS and RNS, and between these and melatonin is a regulatory key center in the responses.
{"title":"Melatonin and reactive oxygen and nitrogen species: a model for the plant redox network","authors":"M. B. Arnao, J. Hernández-Ruiz","doi":"10.32794/11250036","DOIUrl":"https://doi.org/10.32794/11250036","url":null,"abstract":"Melatonin (N-acetyl-5-methoxytryptamine) was discovered in plants in 1995; since then numerous functions have been attributed to this molecule in vascular plants. In addition to its recognized role as a universal antioxidant, other relevant functions have been studied in plants such as its rhizogenic- and vegetative-growth effects, protection against leaf senescence and influences on photosynthesis and on the stomatal apparatus. Also, melatonin has a protective role in stress situations (biotic and abiotic), acting as an osmoregulation and a metabolic corrector when confronted with different stresses. One of the most outstanding aspects is the involvement of melatonin as a multi-signaling molecule in plants. The dual roles of melatonin in physiological stress situations involve both its direct action (free of receptor action) as an antioxidant and its role as a regulator of gene expression. Its relationship with central elements of the plant redox network such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the regulation of relevant elements is discussed. All recent data on melatonin are incorporated to present an updated model, where the balance between ROS and RNS, and between these and melatonin is a regulatory key center in the responses. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86459933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cyclic 3-hydroxymelatonin (c3OHM) is a major metabolite of melatonin in plants produced by the enzymatic action of melatonin 3-hydroxylase (M3H). However, the function of c3OHM in plants is unclear. Here, we report that M3H mRNA and c3OHM levels display diurnal rhythms with peaks at night, but not in a circadian manner. This diurnal rhythmicity occurred predominantly in the late vegetative growth stage (8 weeks after germination), but was absent in the early vegetative growth stage. Transgenic rice plants overexpressing or underexpressing M3H were generated to investigate the physiological roles of diurnal production of c3OHM. The M3H-overexpression (OE) line exhibited higher M3H activity and c3OHM production than the wild-type, and vice versa for the M3H‑underexpression rice (RNAi). The seedling growth phenotype of the OE and RNAi lines was comparable to that of the wild-type but exhibited pleiotropic phenotypic defects at the reproductive stage, such as decreased height, biomass, grain yield, and fertility. Of note, the OE rice showed significantly increased numbers of secondary tillers and panicles. The increase in tiller number of the OE line was linked to increased expression of tiller-related genes, such as MOC1 and TB1, suggesting that the diurnal rhythm of c3OHM production is associated with the tiller number, a pivotal agronomic trait governing grain yield in rice.
{"title":"Cyclic 3-hydroxymelatonin exhibits diurnal rhythm and cyclic 3-hydroxymelatonin overproduction increases secondary tillers in rice by upregulating MOC1 expression","authors":"Geun-Hee Choi, K. Back","doi":"10.32794/11250034","DOIUrl":"https://doi.org/10.32794/11250034","url":null,"abstract":"Cyclic 3-hydroxymelatonin (c3OHM) is a major metabolite of melatonin in plants produced by the enzymatic action of melatonin 3-hydroxylase (M3H). However, the function of c3OHM in plants is unclear. Here, we report that M3H mRNA and c3OHM levels display diurnal rhythms with peaks at night, but not in a circadian manner. This diurnal rhythmicity occurred predominantly in the late vegetative growth stage (8 weeks after germination), but was absent in the early vegetative growth stage. Transgenic rice plants overexpressing or underexpressing M3H were generated to investigate the physiological roles of diurnal production of c3OHM. The M3H-overexpression (OE) line exhibited higher M3H activity and c3OHM production than the wild-type, and vice versa for the M3H‑underexpression rice (RNAi). The seedling growth phenotype of the OE and RNAi lines was comparable to that of the wild-type but exhibited pleiotropic phenotypic defects at the reproductive stage, such as decreased height, biomass, grain yield, and fertility. Of note, the OE rice showed significantly increased numbers of secondary tillers and panicles. The increase in tiller number of the OE line was linked to increased expression of tiller-related genes, such as MOC1 and TB1, suggesting that the diurnal rhythm of c3OHM production is associated with the tiller number, a pivotal agronomic trait governing grain yield in rice. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73046138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Low back pain (lumbar pain) due to injury of or damage to intervertebral discs is common in all societies. The loss of work time as a result of this problem is massive. Recent research suggests that melatonin may prevent or counteract intervertebral disc damage. This may be especially relevant in aging populations given that endogenous melatonin, in most individuals, dwindles with increasing age. The publications related to melatonin and its protection of the intervertebral disc are reviewed herein, including definition of some molecular mechanisms that account for melatonin’s protective actions.
{"title":"Melatonin: Protection of the Intervertebral Disc","authors":"R. Reiter, S. Rosales‐Corral, Ramaswamy Sharma","doi":"10.32794/mr11250028","DOIUrl":"https://doi.org/10.32794/mr11250028","url":null,"abstract":" Low back pain (lumbar pain) due to injury of or damage to intervertebral discs is common in all societies. The loss of work time as a result of this problem is massive. Recent research suggests that melatonin may prevent or counteract intervertebral disc damage. This may be especially relevant in aging populations given that endogenous melatonin, in most individuals, dwindles with increasing age. The publications related to melatonin and its protection of the intervertebral disc are reviewed herein, including definition of some molecular mechanisms that account for melatonin’s protective actions. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"108 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91480333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jose Sinesio-Jr, Paula Bargi-Souza, R. Matos, Eduardo Almeida Leite, D. Buonfiglio, Jéssica Andrade-Silva, L. C. Motta-Teixeira, R. Curi, M. Young, J. Cipolla-Neto, R. A. Peliciari-Garcia
Diabetes increases risk of various comorbidities, including retinopathy, neuropathy, and cardiovascular disease, comprising both ischemic and non-ischemic cardiomyopathy. Cardiac dysfunction during diabetes is associated with perturbations at histologic, metabolic, biochemical and molecular levels. The circadian clock is misaligned in multiple organs during diabetes, including the heart. Such alterations in clock function have been postulated to play a causal role in cardiac dysfunction even though the mechanisms leading to circadian misalignment are currently unknown. Melatonin has been reported to alter heart circadian clock components and its circulating levels are decreased during diabetes. These observations led to the hypothesis that decreased melatonin levels during diabetes could be related to mismanagement of the heart clock. To evaluate this hypothesis, in the current study male Wistar and non-obese type 2 diabetic Goto-Kakizaki (GK) rats were given melatonin supplementation in their drinking water during the dark phase (for 12-wks), followed by assessment of clock component and the mRNA expression of the clock-controlled genes in the hearts of these animals. Melatonin supplementation significantly altered mRNA expression of targeted genes in both euglycemic and diabetic rat hearts. Collectively, under the condition of diabetes, the jeopardized pineal melatonin synthesis with misalignment of cardiac circadian clock components may likely mediate heart metabolic dysfunction, and/or even cause cardiovascular diseases.
{"title":"Melatonin and the heart circadian clock of euglycemic and type 2 diabetic male rats: a transcriptional evaluation","authors":"Jose Sinesio-Jr, Paula Bargi-Souza, R. Matos, Eduardo Almeida Leite, D. Buonfiglio, Jéssica Andrade-Silva, L. C. Motta-Teixeira, R. Curi, M. Young, J. Cipolla-Neto, R. A. Peliciari-Garcia","doi":"10.32794/11250035","DOIUrl":"https://doi.org/10.32794/11250035","url":null,"abstract":"Diabetes increases risk of various comorbidities, including retinopathy, neuropathy, and cardiovascular disease, comprising both ischemic and non-ischemic cardiomyopathy. Cardiac dysfunction during diabetes is associated with perturbations at histologic, metabolic, biochemical and molecular levels. The circadian clock is misaligned in multiple organs during diabetes, including the heart. Such alterations in clock function have been postulated to play a causal role in cardiac dysfunction even though the mechanisms leading to circadian misalignment are currently unknown. Melatonin has been reported to alter heart circadian clock components and its circulating levels are decreased during diabetes. These observations led to the hypothesis that decreased melatonin levels during diabetes could be related to mismanagement of the heart clock. To evaluate this hypothesis, in the current study male Wistar and non-obese type 2 diabetic Goto-Kakizaki (GK) rats were given melatonin supplementation in their drinking water during the dark phase (for 12-wks), followed by assessment of clock component and the mRNA expression of the clock-controlled genes in the hearts of these animals. Melatonin supplementation significantly altered mRNA expression of targeted genes in both euglycemic and diabetic rat hearts. Collectively, under the condition of diabetes, the jeopardized pineal melatonin synthesis with misalignment of cardiac circadian clock components may likely mediate heart metabolic dysfunction, and/or even cause cardiovascular diseases.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89225706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melatonin is present in numerous phototrophic eukaryotes, not only in plants in the meaning of Archaeplastida or of Viridiplantae. It is also formed in members of other superclades, such as Excavata and SAR clade. Typically, their respective phototrophs have acquired chloroplasts from phototrophic eukaryotes, either by taking them up as endosymbionts or by chloroplast capturing. It has been the aim of this overview to trace the phylogenetic relationships between the various phototrophs according to actual, genetically based taxonomy. This includes the consideration of primary heterotrophs that also exist within the same groups and some secondary heterotrophs that have lost functional chloroplasts. The presence of melatonin in these different taxa is discussed under the aspects of its cyanobacterial or α-proteobacterial origins, as transmitted by plastidial or mitochondrial ancestors, or by horizontal gene transfer. Peculiarities of melatonin metabolism that have evolved in some of these groups are also addressed.
{"title":"Melatonin in the evolution of plants and other phototrophs","authors":"R. Hardeland","doi":"10.32794/mr11250029","DOIUrl":"https://doi.org/10.32794/mr11250029","url":null,"abstract":"Melatonin \u0000is present in numerous phototrophic eukaryotes, not only in plants in the \u0000meaning of Archaeplastida or of Viridiplantae. It is also formed in members of \u0000other superclades, such as Excavata and SAR clade. Typically, their respective \u0000phototrophs have acquired chloroplasts from phototrophic eukaryotes, either by \u0000taking them up as endosymbionts or by chloroplast capturing. It has been the \u0000aim of this overview to trace the phylogenetic relationships between the \u0000various phototrophs according to actual, genetically based taxonomy. This \u0000includes the consideration of primary heterotrophs that also exist within the \u0000same groups and some secondary heterotrophs that have lost functional \u0000chloroplasts. The presence of melatonin in these different taxa is discussed \u0000under the aspects of its cyanobacterial or α-proteobacterial origins, as \u0000transmitted by plastidial or mitochondrial ancestors, or by horizontal gene \u0000transfer. Peculiarities of melatonin metabolism that have evolved in some of \u0000these groups are also addressed.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86811640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Pal, B. Bhattacharjee, A. Chattopadhyay, D. Bandyopadhyay
The excessive production of free radicals and/or reactive oxygen species (ROS) in gastrointestinal (GI) tract leads to oxidative damages in GI tissues with development of varied pathological conditions and clinical symptoms. Many endogenous as well as exogenous factors are involved in such pathogenesis, herein, focus was given to the factors of metal toxicity, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion, consumption of high fat diet and alcohol, and different pathological conditions and diseases. Since ROS is more or less involved in the GI damages caused by these factors, therefore attempts have been made to develop appropriate therapeutic agents that possess antioxidant properties. Being a potent antioxidant and free radical scavenger, melatonin was suggested as a potent therapeutic answer to these GI damages. The discovery of different binding sites and receptors of melatonin in the GI tissues further proves its local actions to protect these tissues from oxidative stress. In the review, we attempt to try our best to summarize the current developments regarding the GI injuries caused by oxidative stress and the potential beneficial effects of melatonin on these injuries. The important molecular mechanisms associated with these changes were also highlighted in the discussion. We hope that this review will provide valuable information to consider melatonin as a suitable molecule used for GI tract protection.
{"title":"Pleiotropic roles of melatonin against oxidative stress mediated tissue injury in the gastrointestinal tract: An overview","authors":"P. Pal, B. Bhattacharjee, A. Chattopadhyay, D. Bandyopadhyay","doi":"10.32794/MR11250027","DOIUrl":"https://doi.org/10.32794/MR11250027","url":null,"abstract":"The excessive production of free radicals and/or reactive oxygen species (ROS) in gastrointestinal (GI) tract leads to oxidative damages in GI tissues with development of varied pathological conditions and clinical symptoms. Many endogenous as well as exogenous factors are involved in such pathogenesis, herein, focus was given to the factors of metal toxicity, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion, consumption of high fat diet and alcohol, and different pathological conditions and diseases. Since ROS is more or less involved in the GI damages caused by these factors, therefore attempts have been made to develop appropriate therapeutic agents that possess antioxidant properties. Being a potent antioxidant and free radical scavenger, melatonin was suggested as a potent therapeutic answer to these GI damages. The discovery of different binding sites and receptors of melatonin in the GI tissues further proves its local actions to protect these tissues from oxidative stress. In the review, we attempt to try our best to summarize the current developments regarding the GI injuries caused by oxidative stress and the potential beneficial effects of melatonin on these injuries. The important molecular mechanisms associated with these changes were also highlighted in the discussion. We hope that this review will provide valuable information to consider melatonin as a suitable molecule used for GI tract protection.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"203 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80255990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melatonin (M) is an endogenous molecule found ubiquitously in animals and plants that helps maintain various biological functions. Unlike animals, plants preferentially synthesize 2-hydroxymelatonin (2M) over M, but the biological functions of 2M remain largely unknown. Here, we found that exogenous foliar application of 2M conferred tolerance against combined cold and drought stress in tobacco (Nicotiana benthamiana), tomato (Solanum lycopersicum L. cv. Micro-Tom), and cucumber (Cucumis sativus L. cv. Baecdadaki), whereas no such tolerance was observed against these stresses applied individually. Accordingly, endogenous 2M was induced in tobacco and tomato leaves in response to combined stress, whereas M levels remained unchanged in tobacco leaves and decreased in tomato leaves. After challenging tobacco and tomato leaves with prohexadione-calcium, an inhibitor of 2M synthesis, 2M levels decreased and led to hypersensitivity to combined stress. Because the gene encoding 2M is found only in land plants, and is absent in cyanobacteria and algae, we propose that 2M may have evolved as aquatic plants invaded land to overcome the stressors of virgin terrestrial environments, such as cold and drought.
褪黑素(Melatonin, M)是一种普遍存在于动植物体内的内源性分子，有助于维持多种生物功能。与动物不同，植物优先合成2-羟褪黑素(2M)而不是M，但2M的生物学功能在很大程度上尚不清楚。在本研究中，我们发现外源叶面施用2M使烟草(Nicotiana benthamiana)、番茄(Solanum lycopersicum L. cv.)和番茄(Solanum lycopersicum L. cv.)对冷旱联合胁迫具有耐受性。黄瓜(Cucumis sativus L. cv.;Baecdadaki)，而单独施加这些应力时，没有观察到这种耐受性。因此，在联合胁迫下，烟草和番茄叶片均诱导了内源2M，而烟草叶片中M水平保持不变，番茄叶片中M水平下降。在向烟草和番茄叶片施加2M合成抑制剂prohexadione-calcium后，2M水平下降，导致对联合胁迫的超敏反应。由于编码2M的基因只存在于陆地植物中，而在蓝藻和藻类中不存在，我们认为2M可能是水生植物入侵陆地以克服原始陆地环境(如寒冷和干旱)的胁迫因素而进化而来的。
{"title":"2-Hydroxymelatonin confers tolerance against combined cold and drought stress in tobacco, tomato, and cucumber as a potent anti-stress compound in the evolution of land plants","authors":"Hye‐Jung Lee, K. Back","doi":"10.32794/MR11250020","DOIUrl":"https://doi.org/10.32794/MR11250020","url":null,"abstract":"Melatonin (M) is an endogenous molecule found ubiquitously in animals and plants that helps maintain various biological functions. Unlike animals, plants preferentially synthesize 2-hydroxymelatonin (2M) over M, but the biological functions of 2M remain largely unknown. Here, we found that exogenous foliar application of 2M conferred tolerance against combined cold and drought stress in tobacco (Nicotiana benthamiana), tomato (Solanum lycopersicum L. cv. Micro-Tom), and cucumber (Cucumis sativus L. cv. Baecdadaki), whereas no such tolerance was observed against these stresses applied individually. Accordingly, endogenous 2M was induced in tobacco and tomato leaves in response to combined stress, whereas M levels remained unchanged in tobacco leaves and decreased in tomato leaves. After challenging tobacco and tomato leaves with prohexadione-calcium, an inhibitor of 2M synthesis, 2M levels decreased and led to hypersensitivity to combined stress. Because the gene encoding 2M is found only in land plants, and is absent in cyanobacteria and algae, we propose that 2M may have evolved as aquatic plants invaded land to overcome the stressors of virgin terrestrial environments, such as cold and drought.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"4590 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74596937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melatonin is a molecule with numerous properties, which are applicable to the treatment of different types of cancers. Experimental in vitro and in vivo studies conducted with human cancer cells or animal models of carcinogenesis, have shown that melatonin enhances apoptosis and inhibits cell proliferation of several human cancer cells, reduces tumor growth rate and its metastases, reduces the side effects of chemotherapy and radiotherapy, decreases the resistance to standard cancer treatments, and potentiates the therapeutic effects of other conventional therapies. These satisfactory results obtained from “bench” need to be studied in clinical trials to verify whether they are applicable to “bedside”. In this article we review the clinical trials carried out in the last 25 years which are focused on the therapeutic use of melatonin in cancer treatment. We conclude that melatonin is an effective adjuvant drug to practically any conventional cancer therapy since it is capable of improving the quality of life of patients, by normalizing sleep and alleviating general symptoms associated with tumor disease and treatment such as pain, asthenia, anorexia, etc. In the particular case of hormone-dependent breast cancer, melatonin's antiestrogenic properties make this indoleamine ideally suited for use in association with other synthetic anti-estrogen agents, as melatonin increases their efficacy while reducing their undesirable effects. Furthermore, melatonin could be an appropriate co-treatment for preventive treatment of breast cancer in people with elevated risk for this kind of neoplasia.
{"title":"Clinical uses of melatonin: evaluation of human trials on cancer treatment.","authors":"Alicia González, Noemi Rueda Revilla, J Sánchez-BarcelóEmilio","doi":"10.32794/MR11250021","DOIUrl":"https://doi.org/10.32794/MR11250021","url":null,"abstract":"Melatonin is a molecule with numerous properties, which are applicable to the treatment of different types of cancers. Experimental in vitro and in vivo studies conducted with human cancer cells or animal models of carcinogenesis, have shown that melatonin enhances apoptosis and inhibits cell proliferation of several human cancer cells, reduces tumor growth rate and its metastases, reduces the side effects of chemotherapy and radiotherapy, decreases the resistance to standard cancer treatments, and potentiates the therapeutic effects of other conventional therapies. These satisfactory results obtained from “bench” need to be studied in clinical trials to verify whether they are applicable to “bedside”. In this article we review the clinical trials carried out in the last 25 years which are focused on the therapeutic use of melatonin in cancer treatment. We conclude that melatonin is an effective adjuvant drug to practically any conventional cancer therapy since it is capable of improving the quality of life of patients, by normalizing sleep and alleviating general symptoms associated with tumor disease and treatment such as pain, asthenia, anorexia, etc. In the particular case of hormone-dependent breast cancer, melatonin's antiestrogenic properties make this indoleamine ideally suited for use in association with other synthetic anti-estrogen agents, as melatonin increases their efficacy while reducing their undesirable effects. Furthermore, melatonin could be an appropriate co-treatment for preventive treatment of breast cancer in people with elevated risk for this kind of neoplasia.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75766406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Chuffa, F. Seiva, M. Cucielo, H. S. Silveira, R. Reiter, L. A. Lupi
Circadian rhythms control most biological processes in every organism and their disruption or an aberrant function in the expression of clock genes are associated with a number of cancers including some hormone-dependent and independent cancers. The processes involved in carcinogenesis and tumor progression are complex, but understanding the daily profiles of the core clock genes and their clock-controlled genes is essential to evaluate specifically the molecular program of the cancer phenotype; this may be helpful in providing a more realistic strategy for both diagnosis and treatment during the course of the disease. Because melatonin production and secretion oscillates rhythmically through the light:dark cycle and is related to the circadian machinery genes (Clock, Bmal1, Periods, and Cryptochromes), its regulatory role on clock genes in cancer cells may bring additional evidence regarding the mechanism(s) by which melatonin is involved. Mechanistically, melatonin acts via proteasome inhibition and sirtuins to indirectly modulate clock genes in cancer; however, melatonin seems to be capable of directly altering the expression of clock genes to affect cancer development. Depending on cancer cell type, melatonin might up or downregulate specific clock genes to control cell cycle, survival, repair mechanisms, etc. In parallel, melatonin exerts pro-apoptotic, anti-proliferative and pro-oxidative effects, metabolic shifting, reduction in neovasculogenesis and inflammation, and restores chemosensitivity of cancer cells. Finally, melatonin improves the life quality of patients. This review focuses on the main functions of melatonin on clock genes, and reviews, from a clinical and experimental standpoint, how melatonin regulates the expression of clock genes in some prevalent cancer types such as breast, prostate, liver, and colon cancers, leukemia and melanoma. We further emphasized possible signaling mechanisms whereby melatonin interferes with clockwork genes and circadian-controlled genes within cancer cells.
{"title":"Clock genes and the role of melatonin in cancer cells: an overview","authors":"L. Chuffa, F. Seiva, M. Cucielo, H. S. Silveira, R. Reiter, L. A. Lupi","doi":"10.32794/MR11250026","DOIUrl":"https://doi.org/10.32794/MR11250026","url":null,"abstract":" Circadian rhythms control most biological processes in every organism and their disruption or an aberrant function in the expression of clock genes are associated with a number of cancers including some hormone-dependent and independent cancers. The processes involved in carcinogenesis and tumor progression are complex, but understanding the daily profiles of the core clock genes and their clock-controlled genes is essential to evaluate specifically the molecular program of the cancer phenotype; this may be helpful in providing a more realistic strategy for both diagnosis and treatment during the course of the disease. Because melatonin production and secretion oscillates rhythmically through the light:dark cycle and is related to the circadian machinery genes (Clock, Bmal1, Periods, and Cryptochromes), its regulatory role on clock genes in cancer cells may bring additional evidence regarding the mechanism(s) by which melatonin is involved. Mechanistically, melatonin acts via proteasome inhibition and sirtuins to indirectly modulate clock genes in cancer; however, melatonin seems to be capable of directly altering the expression of clock genes to affect cancer development. Depending on cancer cell type, melatonin might up or downregulate specific clock genes to control cell cycle, survival, repair mechanisms, etc. In parallel, melatonin exerts pro-apoptotic, anti-proliferative and pro-oxidative effects, metabolic shifting, reduction in neovasculogenesis and inflammation, and restores chemosensitivity of cancer cells. Finally, melatonin improves the life quality of patients. This review focuses on the main functions of melatonin on clock genes, and reviews, from a clinical and experimental standpoint, how melatonin regulates the expression of clock genes in some prevalent cancer types such as breast, prostate, liver, and colon cancers, leukemia and melanoma. We further emphasized possible signaling mechanisms whereby melatonin interferes with clockwork genes and circadian-controlled genes within cancer cells. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"285 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76873575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Two important hubs have emerged as cutting edge areas of research across a diverse array of medical conditions, the gut microbiome and mitochondria. This article highlights the role of melatonin in modulating changes in both the gut and mitochondria. The gut microbiome, especially via its production of the small chain fatty acid, butyate, can have a significant impact on immune inflammatory processes. Lower levels of butyrate producing bacteria can increase gut permeability, thereby increasing immune-inflammatory activity. Butyrate may also modulate immune and other cells via the regulation of the content of exosomes from intestinal epithelial cells. Butyrate also induces N-acetylserotonin and melatonin synthesis in the gut, suggesting that some of the effects of butyrate may be mediated via its induction of the melatonergic pathway. The induction of melatonin by butyrate may feed back on the microbiome via melatonin increasing gut bacteria swarming, as well as melatonin optimizing gut barrier and mitochondria functioning. As butyrate readily crosses into the circulation it is likely that the immune- and glia-dampening effects of butyrate also involve the induction of melatonin in these reactive cells. Butyrate also positively modulates mitochondria functioning, suggesting that butyrate, both directly and via melatonin, will have significant impacts on gut, immune, glia and other cells, via mitochondria regulation. Other factors that act to regulate melatonin, including dietary factors and stress, will therefore act to modulate many of butyrate's effects. The regulation of melatonin at these two important hubs has significant treatment and classification implications across a wide array of medical conditions. Overall, gut dysbiosis has a significant impact on central and systemic homeostasis, via decreased butyrate and melatonin driving suboptimal mitochondria functioning. This has implications for the pathoetiology and pathophysiology of a host of medical conditions associated with gut dysbiosis and decreased melatonin production.
{"title":"Mitochondria and the Gut as crucial hubs for the interactions of melatonin with sirtuins, inflammation, butyrate, tryptophan metabolites, and alpha 7 nicotinic receptor across a host of medical conditions.","authors":"G. Anderson","doi":"10.32794/MR11250022","DOIUrl":"https://doi.org/10.32794/MR11250022","url":null,"abstract":"Two important hubs have emerged as cutting edge areas of research across a diverse array of medical conditions, the gut microbiome and mitochondria. This article highlights the role of melatonin in modulating changes in both the gut and mitochondria. The gut microbiome, especially via its production of the small chain fatty acid, butyate, can have a significant impact on immune inflammatory processes. Lower levels of butyrate producing bacteria can increase gut permeability, thereby increasing immune-inflammatory activity. Butyrate may also modulate immune and other cells via the regulation of the content of exosomes from intestinal epithelial cells. Butyrate also induces N-acetylserotonin and melatonin synthesis in the gut, suggesting that some of the effects of butyrate may be mediated via its induction of the melatonergic pathway. The induction of melatonin by butyrate may feed back on the microbiome via melatonin increasing gut bacteria swarming, as well as melatonin optimizing gut barrier and mitochondria functioning. As butyrate readily crosses into the circulation it is likely that the immune- and glia-dampening effects of butyrate also involve the induction of melatonin in these reactive cells. Butyrate also positively modulates mitochondria functioning, suggesting that butyrate, both directly and via melatonin, will have significant impacts on gut, immune, glia and other cells, via mitochondria regulation. Other factors that act to regulate melatonin, including dietary factors and stress, will therefore act to modulate many of butyrate's effects. The regulation of melatonin at these two important hubs has significant treatment and classification implications across a wide array of medical conditions. Overall, gut dysbiosis has a significant impact on central and systemic homeostasis, via decreased butyrate and melatonin driving suboptimal mitochondria functioning. This has implications for the pathoetiology and pathophysiology of a host of medical conditions associated with gut dysbiosis and decreased melatonin production. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"186 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83044645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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